Our anatomical, behavioral and physiological studies have demonstrated that the analgesia produced by opiates and electrical brain stimulation requires descending connections from the brainstem to spinal cord pain transmission neurons. The descending connections travel in the dorsolateral funiculus (DLF) and a large component arises in the medullary nucleus raphe magnus (NRM). Electrical stimulation of NRM produces behavioral analgesia and, via the DLF, inhibits spinal dorsal horn neurons. The marked overlap between the terminal fields of NRM axons in cat and the DNS distribution of the opioid peptides (endorphins) in the rat raises the possibility that NRM is part of an endogenous analgesia system which involves the endorphins. We propose to study the mechanisms of analgesia production at several levels of the nervous system. Immunohistochemical methods will be used to assess the distribution of enkephalin in the cat. We will examine the spinal mechanism of the inhibition produced by NRM stimulation using two novel measures: the terminal excitability of identified, single unmyelinated primary afferents and the activity of substantia gelatinosa neurons. We will also study the source of inputs to NRM using retrograde tracing methods and by recording the responses of NRM neurons to natural stimulation and to systemic and/or intracerebral injection of opiate agonists and antagonists. Our HRP analysis of descending brainstem connections involved in analgesia has revealed a major projection via the DLF from the catecholamine-rich subcoeruleus (SC) region. An autoradiographic study of the efferent projections from this region will provide an important comparative analysis of descending NRM-serotonergic and SC-noradrenergic terminals in spinal cord. Taken together, these studies will advance our understanding of the anatomical substrates and physiological mechanism of action of endogenous pain control systems.